Typically, biopharmaceutical proteins such as monoclonal antibodies (mAbs) and immunoglobulin fusion proteins (e.g., immunoadhesion proteins) are produced by recombinant DNA technology in mammalian cell expression systems. In order to guarantee the reproducible clinical performance of a biopharmaceutical product, manufacturers have to deliver a product of consistent and reproducible quality. It is well-established that molecular alterations can occur during every stage of the manufacturing process and those aspects of the upstream unit operations, including cell culture conditions, exposure to various buffers and solutions during the purification process and storage conditions, can each introduce heterogeneity into a mAb or Fc-fusion protein product.
Some of the molecular alterations can alter a quality attribute of a biopharmaceutical product, resulting in an undesirable change in the identity, strength or purity of the product. In addition, process-related heterogeneities can produce variant proteins characterized by alterations in either the size, chemical/charge or conformation of a biopharmaceutical protein. Furthermore, depending upon the type of host cell that is used, and the particular amino acid sequence of the protein, additional heterogeneity may also be introduced as a consequence of intracellular processes, such as post-translational modifications.
The primary goal of formulation development is to provide a pharmaceutical composition that will support the stability of a biopharmaceutical protein during all stages of its production, storage, shipping and use. The process of formulation development for an innovative biopharmaceutical protein, or a biosimilar monoclonal antibody (mAb) or a recombinant Fc-containing fusion protein (Fc-fusion protein), is essential to its safety, clinical efficacy and commercial success.
The biopharmaceutical protein etanercept (TNFR:Fc) is a Fc-fusion protein which is known to be susceptible to misfolding, fragmentation and aggregation. Therefore, there is a need for stabilizing liquid (aqueous) formulations capable of mitigating these issues when a pharmaceutical composition comprising etanercept is stored or marketed as a liquid product.